The protein product of the MET proto-oncogene, c-Met, a receptor tyrosine kinase (RTK), is a prototype for the c-Met RTK subfamily and is activated by the ligand hepatocyte growth factor (HGF; scatter factor). Activation of the HGF/c‐Met pathway causes tumor progression, invasion, and metastasis[3]. Moreover, the c-Met signaling pathway engages with other pathways, including that of the EGFR/human EGFR/MAPK/ERK pathway and can also promote angiogenesis through interaction with the VEGF and VEGF receptor (VEGFR) pathway. In addition, c-Met signaling can downregulate the antiangiogenic thrombospondin-1 and upregulate VEGF and upregulation of HGF and c-Met occurs after VEGF inhibition. Golvatinib (E7050, Eisai) is a highly potent, small-molecule, ATP-competitive inhibitor of c-Met and multiple members of the Eph receptor family, as well as c-Kit and Ron, with an IC50 for c-Met of 0.001 μM[4]. E7050 inhibits both c-Met and vascular endothelial growth factor receptor (VEGFR)-2 and inhibits phosphorylation of both c-Met and VEGFR-2. E7050 also potently represses the growth of both c-Met amplified tumor cells and endothelial cells stimulated with either HGF or VEGF. In a vitro study, MKN45 (gastric), SNU-5 (gastric), Hs746T (gastric), EBC-1 (lung), MKN74 (gastric), SNU-1 (gastric), A549 (lung) cell lines were treated with c-Met nonselective inhibitor E7050 at a dose ranging in 50-200 mg/kg to induce tumor regression and disappearance, indicating that E7050 is an efficient inhibitor of c-Met by inhibited phosphorylation of c-Met in tumors. In a vivo study, After different tumor cells were implanted subcutaneously (s.c.) into the mice respectively, E7050 was administered orally once a day at dose ranging from 25 mg/kg to 200 mg/kg for 8 to 15 days, suggesting that E7050 showed inhibition of the phosphorylation of c-Met in tumors, and strong inhibition of tumor growth and tumor angiogenesis. In a peritoneal dissemination model, MKN45 cells were inoculated intraperitoneally into nude mice and treated with E7050 at dose ranging from 25 mg/kg to 100 mg/kg for 6 days. E7050 showed an antitumor effect against peritoneal tumors as well as a significant prolongation of lifespan in treated mice. The results indicate that E7050 is a potent inhibitor of c-Met and VEGFR-2 and has therapeutic potential for the treatment of cancer[3].
作用机制
Golvatinib binds to the MET enzyme with a 2-aminopyridine hinge binder.
Golvatinib 细胞实验
Cell Line
Concentration
Treated Time
Description
References
A549 cells
8.14 ± 0.45 µM
72 h
To evaluate the antitumor activity of Golvatinib against A549 cells, the results showed an IC50 value of 8.14 ± 0.45 µM
Molecules. 2019 Dec 18;25(1):10.
HeLa cells
15.17 ± 0.17 µM
72 h
To evaluate the antitumor activity of Golvatinib against HeLa cells, the results showed an IC50 value of 15.17 ± 0.17 µM
Molecules. 2019 Dec 18;25(1):10.
MCF-7 cells
16.91 ± 0.29 µM
72 h
To evaluate the antitumor activity of Golvatinib against MCF-7 cells, the results showed an IC50 value of 16.91 ± 0.29 µM
Molecules. 2019 Dec 18;25(1):10.
HUVECs
30 nM
3 days
To investigate the effect of Golvatinib on HGF-induced resistance to Lenvatinib, results showed that the combination of Golvatinib with Lenvatinib significantly inhibited the proliferation of HUVECs
Cancer Sci. 2014 Jun;105(6):723-30.
Golvatinib 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Nude mice
K1 ⁄Ang2 and AN3CA xenograft models
Oral
100 mg/kg
Once daily until the end of the experiment
Golvatinib combined with lenvatinib showed antitumor effects in both K1 ?Ang2 and AN3CA models, significantly reducing blood perfusion and increasing apoptosis.
Cancer Sci. 2015 Feb;106(2):201-7
Nude mice
K1/Ang2 and AN3CA xenograft models
Oral
100 mg/kg
Once daily until the end of the experiment
To evaluate the effect of Golvatinib in combination with Lenvatinib on tumor growth. Results showed that the combination of Golvatinib and Lenvatinib significantly inhibited tumor growth, leading to severe perfusion disorder and massive apoptosis.
Cancer Sci. 2015 Feb;106(2):201-7
Nude mice
Human tumor xenograft models
Oral
100 mg/kg
Once daily for 8-21 days
To investigate the antitumor effect of Golvatinib in combination with Lenvatinib on HGF-overexpressing tumors, results showed that the combination therapy significantly inhibited tumor growth
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